The present invention is directed at pharmaceutical compositions and formulations, and methods of making and administering such compositions and products, for use in the treatment of brain tumours, including glioma such as diffuse intrinsic pontine glioma (DIPG).
Histone deacetylase (HDAC) inhibitors show significant potential for the treatment of various cancers. Panobinostat (Farydak®, LBH-589, 2-(E)-N-hydroxy-3-[4[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide) is a non-selective HDAC inhibitor used in the treatment of multiple myeloma. Combination therapy of panobinostat and radiation has been proposed for the treatment of solid tumours (WO2007/050655). However, hydroxamate compounds, including panobinostat, exhibit poor aqueous solubility and stability (WO2009/039226). Panobinostat formulations have been proposed that employ at least one alcohol to reduce oxidation and hydrolysis (WO2008/086330).
Wehrmann et al., PLOS ONE, 2012, Vol. 7, Issue 10, e48561, describe lowering of intracellular cholesterol levels in Niemann-Pick Type C Fibroblasts by vorinostat, panobinostat, beta-cyclodextrin and combinations thereof.
Grasso et al., Nature Medicine, 2015, Vol. 21, No. 6, pp. 555-559, report that the multi-histone deacetylase inhibitor, panobinostat, demonstrated therapeutic efficacy both in vitro and in DIPG orthotopic xenograft models. However, panobinostat was formulated in dimethyl sulphoxide (DMSO) for convection-enhanced delivery (CED) to the xenograft tumour-bearing mice. DMSO is a mild oxidising agent and has a number of shortcomings for clinical use in humans.
WO2015/191931 describes pharmaceutical compositions containing a hydrophobic drug (which may be an HDAC inhibitor), prodrug thereof, salt thereof, isoform thereof, or a combination thereof; cyclodextrin, prodrug thereof, salt thereof, of combination thereof; polyethylene glycol, propylene glycol, or combination thereof; and a pharmaceutically acceptable carrier, as well as medical uses thereof, including in the treatment of a brain disease.
WO2008/002862 describes pharmaceutical compositions containing inhibitors of histone deacetylase and B vitamins and medical uses thereof, including in the treatment of proliferative disorders.
Hockly et al., PNAS, 2003, Vol. 100(4), pp. 2041-2046, describes treatment of a mouse model of Huntington's disease using the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA), administered orally.
US2013177499 proposes use of bacterially derived minicells as delivery vehicles for active agents against brain tumours.
WO2013/135727 describes a method for treatment of glioma by convection enhanced delivery (CED) using a composition of carboplatin in artificial cerebrospinal fluid (CSF).
There remains an unmet need for pharmaceutical formulations that are stable and amenable to central administration (e.g. via CED) for the treatment of brain tumours, including glioma. The present invention addresses these and other needs.